Cardiovascular disease is the leading cause of death in the western world. Coronary artery disease can lead to prolonged or irreversible episodes of cardiac ischemia that result in myocardial infarction (MI) which is associated with a high rate of mortality. See Lucchesi, Myocardial reperfusion injury—Role of free radicals and mediators of inflammation. in: Heart Physiology and Pathophysiology, 4th ed. Chapter 65, pp 1181-1220, Academic Press (2001); Pfeffer & McMurray, Circulation 2002, 105, 2577-2579.
Ischemia is an acute condition that results from insufficient flow of oxygenated blood to a part of the body. The reduced flow is typically caused by blockage of a vessel by an embolus (blood clot); the blockage of a vessel due to atherosclerosis; the breakage of a blood vessel (a bleeding stroke); the blockage of a blood vessel due to vasoconstriction such as occurs during vasospasms and possibly, during transient ischemic attacks (TIA) and following subarachnoid hemorrhage. Conditions in which ischemia occurs further include myocardial infarction; trauma; and during cardiac and thoracic surgery and neurosurgery (blood flow needs to be reduced or stopped to achieve the aims of surgery). Procedures that can cause ischemia include coronary thrombolysis, coronary angioplasty (with or without stent placement), and coronary artery bypass grafts. During myocardial infarct, stoppage of the heart or damage occurs which reduces the flow of blood to organs, and ischemia results. Cardiac tissue itself is also subjected to ischemic damage. During various surgeries, reduction of blood flow, clots or air bubbles generated can lead to significant ischemic damage.
During an ischemic event, there is a gradation of injury that arises from the ischemic site. Cells at the site of blood flow restriction, undergo necrosis and form the core of a lesion. A penumbra is formed around the core where the injury is not immediately fatal but progresses slowly toward cell death. This progression to cell death may be reversed upon reestablishment of blood flow within a short time of the ischemic event.
Use of an estrogen compound such as 17α-estradiol or 17β-estradiol, has been reported to be useful in the prevention and treatment of ischemic damage. See, U.S. Pat. Nos. 6,350,739; 6,339,078; 6,326,365; 5,877,169; Delyani et al., J. Mol. Cell Cardiol. 1996, 28, 1001-1008; Hale, et al., Am. Heart J. 1996, 132, 258-262; Kim, et al., Circulation 1996, 94, 2901-2908; Li et al., 2000, J. Pharmacol Exp. Ther. 293, 592-598; Node, et al., FASEB J. 1997, 11, 793-799.
17-β-Estradiol, however, strongly stimulates creatine kinase expression as well as proliferative effects on uterine and breast tissue. Thus, in ERT some potential unwanted side effects, such as an increase risk of cardiovascular events in the first year of use, have been demonstrated (Hulley, S. et. al., J. Am. Med. Assoc., 1998, 280, 605) as well as proliferative effects on uterine and breast tissue. Ligands that exhibit the benefit of ERT without the unwanted side effects have been the subject of recent publications.
Current therapies including the use of vasodilators, anti-thrombotics/thrombolytics, β-blockers and coronary artery bypass graft are used pre and post MI to maintain/restore coronary blood flow and limit oxygen demand. However, there is an unmet need for therapies that can be used to directly inhibit the development of permanent cardiac injury during a myocardial infarction.